Delivery system for in situ forming foams and methods of using the same

ABSTRACT

Delivery systems for in situ forming foam formulations are provided. The devices may include various actuation mechanisms and may entrain air into fluid formulation components in a variety of ways, including mixing with air and the addition of compressed gas.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Application Ser. No. 61/852,051filed Mar. 15, 2013 entitled “Delivery System for In Situ Forming Foamsand Methods of Using the Same,” and further claims priority to U.S.application Ser. No. 13/209,020 filed Aug. 12, 2011 entitled “In SituForming Hemostatic Foam Implants,” which in turn is acontinuation-in-part of U.S. application Ser. No. 12/862,362 filed Aug.24, 2010 entitled “Systems and Methods Relating to Polymer Foams.” Theentire disclosure of each of the foregoing applications is herebyincorporated by reference for all purposes.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with Government support under award nos.W911NF-10-C-0089 and W911NF-12-C-0066 awarded by the Defense AdvancedResearch Projects Agency (DARPA). The Government has certain rights inthe invention.

TECHNICAL FIELD

The present invention relates to medical devices for the delivery of insitu forming foams to patients.

BACKGROUND

In situ forming polymer foams, such as the Arsenal Foam Technologycommercialized by Arsenal Medical (Watertown, Mass.), have a number ofimportant biomedical applications, including the prevention or treatmentof hemorrhage, particularly from non-compressible ordifficult-to-visualize wounds, vascular embolization, arteriovenousmalformation, AV fistulas, space filling and bulking (e.g. followingsurgical resection, or for cosmetic purposes), prevention of tissueadhesion, hernia repair, prevention or treatment of reflux, andtemporary or permanent occlusion of body lumens for a variety ofapplications including sterilization, prevention of calculus migrationduring lithotripsy, and other applications. The diversity ofapplications for in situ forming foams reflects significant advantagespossessed by such foams relative to existing technology, including,without limitation their incorporation of well characterized,biocompatible materials; the ability to deliver in situ forming foams toclosed cavities, for example intravascularly; the ability to deliver insitu forming foams to difficult-to-access body sites; the ability of insitu forming foams to expand into empty space or into space filled withblood, and the ability of the foam to fill a body cavity.

In situ forming foams are typically generated by delivering and mixingmultiple liquid-phase components (such as a polyol component and anisocyanate component, which form a polyurethane foam). Each suchliquid-phase component may comprise multiple different materials oragents that determine the mechanical properties of the foam and/or thekinetics of foam formation. Pores within the foam may be formed by ablowing reaction and/or by the entrainment of gas before or during foamformation. While blowing agents are effective to drive the foaming andexpansion of in-situ forming foams, blowing agents or their byproductsmay be toxic, and entrained gas may be preferred for applications inwhich such toxicity is preferably avoided.

In situ forming foams are particularly well suited to treating injuriesin challenging settings such as in remote settings, and on thebattlefield. However, in spite of their advantages, in situ formingfoams have not been widely used because of the technical challengesassociated with developing suitable in-situ foaming formulations fordifferent applications and delivering such formulations to specificanatomical sites. Additionally, to maximize their efficacy inchallenging settings such as on the battlefield, delivery systems for insitu forming foams should preferably be easy to assemble, provide a safeway to access the target site in the body, have a minimal number ofparts, and rapidly aerate, mix, and deliver volumes of approximately80-200 mL of in situ foaming formulations to patients. Whilelow-viscosity materials can be aerated by simple shaking, gasentrainment poses a significant challenge in higher viscosityformulations, which may be necessary to generate foams having desirablephysical and therapeutic characteristics.

There is, accordingly, a need in the art for delivery systems forefficiently delivering viscous gas-entrained in situ forming foamformulations to sites of interest in patients' bodies in non-clinicalsettings such as on the battlefield.

BRIEF DESCRIPTION OF THE INVENTION

The present invention addresses the need described above by providing,in one aspect, a medical device for the delivery of in situ formingfoams to sites on or within the body. The medical device includes afluid cartridge that includes multiple fluid chambers and multiplepistons, and the volume of each fluid chamber is determined by theposition of a piston. At least one chamber includes an impeller, and thedevice also includes an actuator to move the impeller and/or the piston,as well as a static mixer that connects to each of the chambers. Theactuator may connect to a piston so it moves the piston in the chamber,and the actuator can be any of a squeeze handle, crank, ratchet, orpiston pump. Moving the actuator once may be sufficient to ejectsubstantially all of the contents of a chamber, or the actuator may needto be moved multiple times. The device can also include a gas cylinderor a motor. The impeller is optionally solid or porous and contacts thewall of the chamber. The static mixer can include a cylindrical outershell with a tapered end that has multiple apertures, plus a lumendefined by the outer shell which contains multiple mixing elements. Themixing elements can be X-grids, beads, or mesh. The medical device isalso optionally mechanically driven such that no electrical or pneumaticparts are used.

In another aspect, the invention relates to methods for treatingpatients that include the steps of providing an activatable deliverydevice loaded with multiple liquid-phase foam forming components, andactivating the delivery device to aerate at least one liquid phasecomponent, then mixing the components to form a gas-entrained foamingcomposition and dispensing the composition into a patient's body cavity.The method optionally includes one or more of the following: thedelivery device can include a selector for selecting the quantity offoaming composition to be delivered to the patient, and the method caninclude using the selector to select such a quantity; activating thedelivery device can comprise actuating a trigger connected to a fluidimpeller that mixes or aerates the components, and activating thetrigger can also cause the ejection of the gas-entrained foamingcomposition from the delivery device; the trigger can be actuated bysqueezing, and the delivery device can also include a lockout to preventejection of the foaming composition prior to aeration of at least oneliquid phase component. The delivery device can also include a tip thatcan be inserted into a patient, and the method can include putting adilator sheath into a body wall of the patient and inserting the tipinto the patient through the dilator sheath. The tip can include astatic mixer, and when the trigger is actuated, the liquid phasecomponents can be forced across the static mixer and out of the tip ofthe delivery device into the patient.

In yet another aspect, the invention relates to methods for entraininggas into the formulation prior to delivery into the body.

In another aspect, the invention relates to a lock out mechanism and aready indicator to prevent a user of a medical device according to theinvention from administering un-aerated formulations to patients.

In still another aspect, the invention relates to a method of mixing thetwo part formulation after air entrainment and prior to the dispensinginto the body.

DESCRIPTION OF THE DRAWINGS

In the drawings, like reference characters refer to like featuresthroughout the various figures. The figures provided herein are notnecessarily drawn to scale, with emphasis being placed on illustrationof the principles of the invention.

FIGS. 1A-B include schematic depictions of a delivery system accordingto certain embodiments of the invention.

FIGS. 2A-B include schematic depictions of a delivery system accordingto certain embodiments of the invention.

FIGS. 3A-C include multiple views of partially disassembled deliverysystems according to the invention.

FIG. 4 includes a view of a delivery system according to certainembodiments of the invention.

FIGS. 5A-G include multiple views of seal plunger assemblies and helicalmesh assemblies according to certain embodiments of the invention.

FIG. 6 includes a schematic depiction of an exemplary site for a skinincision to access the abdominal cavity of a patient according tocertain embodiments of the invention.

FIG. 7 includes a view of a Veress needle with a Dilator Sheath.

FIG. 8 includes a schematic view of a dilating nozzle according tocertain embodiments of the invention.

FIGS. 9A-C include multiple views of static mixing tips according tocertain embodiments of the invention.

FIGS. 10A-B include schematic depictions of a delivery system accordingto certain embodiments of the invention.

FIGS. 11A-B include views and a schematic depiction of a delivery systemaccording to certain embodiments of the invention.

FIG. 12 includes a schematic depiction of a delivery system according tocertain embodiments of the invention.

FIGS. 13A-B include views of a delivery system according to certainembodiments of the invention.

FIGS. 14A-B include schematic depictions of a delivery system accordingto certain embodiments of the invention.

FIG. 15 includes a depiction of the steps of using a delivery systemaccording to certain embodiments of the invention.

FIG. 16 includes schematic depictions and a photograph of deliverysystems according to certain embodiments of the invention.

FIGS. 17A-D include schematic depictions and a photograph of deliverysystems according to certain embodiments of the invention.

FIG. 18 includes schematic depictions and a photograph of deliverysystems according to certain embodiments of the invention.

FIG. 19 includes schematic depictions and a photograph of deliverysystems according to certain embodiments of the invention.

FIGS. 20A-B include schematic depictions and a photograph of deliverysystems according to certain embodiments of the invention.

FIGS. 21A-C include depictions of exemplary reducing gears compatiblewith certain embodiments of the invention.

FIG. 22 includes a depiction of an exemplary reducing gear compatiblewith certain embodiments of the invention.

FIGS. 23A-F include views of exemplary impellers compatible with certainembodiments of the invention.

FIGS. 24A-C include views of exemplary impellers compatible with certainembodiments of the invention.

FIGS. 25A-B include schematic depictions of an exemplary chamber withconcentric fluid subchambers according to certain embodiments of theinvention.

FIG. 26 includes schematic depictions of an exemplary distal chambersurface and an exemplary concentric mixing plate arrangement accordingto certain embodiments of the invention.

FIGS. 27A-D include depictions of fluid sub-chambers according toembodiments of the invention

FIG. 28 includes depictions of mixing plates according to certainembodiments of the invention.

FIGS. 29A-E include photographs of prototype mixing plates according tocertain embodiments of the invention.

FIGS. 30A-E include schematic depictions of exemplary fluid canistersand iris mixing arrangements for delivery systems according to certainembodiments of the invention.

FIGS. 31A-D include schematic depictions of exemplary iris mixingarrangements for delivery systems

FIGS. 32A-C include pictures of exemplary spring-loaded cutting needlesaccording to certain embodiments of the invention.

FIGS. 33A-E include pictures of exemplary delivery systems withmotorized mixers according to certain embodiments of the invention.

FIGS. 34A-B include schematic depictions of exemplary delivery systemswith motorized mixers according to certain embodiments of the invention.

FIG. 35 includes a schematic depiction of an exemplary connector forengaging a mixing tip with a motorized mixer according to certainembodiments of the invention.

FIGS. 36A-B include photographs of exemplary multi-prong deliverycatheter tips according to certain embodiments of the invention.

FIGS. 37A-C include photographs of exemplary delivery catheter tipsaccording to certain embodiments of the invention.

FIGS. 38A-B include photographs of assembled and collapsed deliverysystems according to certain embodiments of the invention.

FIG. 39 includes a photograph of a cartridge including a lockoutmechanism.

FIGS. 40A-B include schematic cross-sectional depictions of a lockoutmechanism in the open and locked positions according to certainembodiments of the invention.

FIGS. 41A-B include photos of an exemplary lock-out and indicatormechanism.

FIGS. 42A-D include photos of an exemplary lock-out and indicatormechanism.

FIG. 43 includes a schematic perspective depiction of a handle assemblyin accordance with embodiments of the invention.

FIG. 44 includes a schematic perspective depiction of a handle assemblywith a dose slider in accordance with embodiments of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The inventors have created an in situ forming foam to treat severeabdominal, junctional and/or pelvic hemorrhage that can be administeredby injecting and mixing together two liquid phases, triggering achemical reaction which causes foaming material to expand and distributethroughout the abdominal cavity. Administration of this foam has beenshown to provide a significant survival advantage in a model of severeabdominal hemorrhage in swine. However, translation of this technologyinto a successful product requires development of delivery system toenable effective administration of foams to treat injuries, and it wouldbe highly desirable for such a system to be functional outside of thehospital setting, for example on the battlefield in a far-forwardenvironment. A successful delivery device is preferably characterized bythe following: (a) compatibility with a safe and simple method to gainentry into the desired body cavity, (b) easy assembly with minimalnumber of components, (c) rapid delivery of the formulation, (d)delivery of the appropriate volume of the liquid phases (80-200 mL), (e)successful mixing of the two liquid phases, (f) a method to easilyentrain air into one of the phases, (g) prevention of deployment ofunaerated formulation, (h) appropriate distribution of the liquid phasesin the cranial, caudal, and lateral directions, (i) ability to selectthe appropriate dose, if required, and (j) biocompatible materials.Disclosed herein are systems and components that can achieve all or partof the above requirements.

Ratchet Mechanism

An exemplary delivery system 100 according to certain embodiments of theinvention includes a dual barrel cartridge 110 comprising two adjacentfluid chambers, each chamber configured to hold one of the liquid phasesA and B. The delivery system 100 also includes a squeezable grip 120, astatic mixing nozzle 130 with a flexible connector 140, and piston pushrods 150A, B for urging the liquid phases from each of the barrels 110A,B of the cartridge 110. This design can have two variants: (1) a singleactuation mechanism 120 (e.g. a squeeze handle) effectuates both airentrainment and formulation deployment, as illustrated in FIG. 1; or (2)two independent actuation mechanisms 120, 121, one for air entrainment(e.g. a crank handle) and a separate one (e.g. a squeeze handle) fordeployment, are built into the design, as shown in FIG. 2. As the grip120 is squeezed, it engages the piston push rods 150A, B, through theuse, for example, of two friction plate and springs and ratchets the rodforward thereby deploying the material. Other means for engaging thepush rods include toothed surfaces, pulleys, and lead screws. A formfactor prototype was created, as shown in FIG. 3, to understandergonomics of the device and a functional prototype, depicted in FIG. 4,was successfully used to deploy in situ forming formulations.

Preferred embodiments of the invention incorporate mechanisms to preventthe deployment of unaerated or partially aerated formulations, whichmechanisms are optionally coupled to an indicator that indicates to auser that the formulation is fully aerated and ready for deployment.Additionally, preferred embodiments of the invention allow users toselect a quantity of aerated formulation that will be delivered to thepatient. These aspects of the invention are described more fully below.

Aeration Mechanism

Air entrainment in one of the liquid phases may be required to create afoam with the desired properties. Generally, at least one fluid chamberof the cartridge will include both a liquid phase and a gas portion(termed a “head”) that is mechanically mixed into the liquid phase inorder to yield a gas-entrained liquid phase. In certain embodiments,entrainment is accomplished through the use of a helical or zig-zag meshassembly 160 within at least one of the fluid barrels 110A or B. Meshesuseful in embodiments of the invention are made of any suitablematerial, including metals (e.g. stainless steel, nitinol) or polymers(e.g. polypropylene). An exemplary helical mesh is shown, at variousangles of rotation, in FIG. 5E. The mesh is formed of a shape memorymaterial, preferably nitinol, which is flexible but resilient enough toresist tearing when used to aerate viscous formulations. The mesh 160 isgenerally planar, and moves through a plurality of turns along thelength of a rod 161. The mesh 160 is also slidably attached to the rod161 so that, as the plunger is advanced through the chamber, the meshcollapses. The mesh 160 fits within the barrel 110A, B such that themesh 160 makes contact with the wall of the barrel. Though not wishingto be bound by theory, it is believed that contact between the mesh andthe barrel improves the efficiency of air entrainment, as it is believedthat such contact prevents air bubbles from moving around the mesh andalong the wall, instead forcing such bubbles to remain in contact themesh as the mesh moves within the liquid phase.

The cartridge 110 is sealed at the end with a plunger 162, which in turnincludes a through lumen for the rod assembly 161 so that the helicalmesh can rotate. O-rings 163 are used as seals to prevent leakage fromthe plunger through the lumen. The cartridge 110 is held by the user atan angle Θ between 0 (vertical) and 90 (horizontal) degrees, preferablybetween 45 and 90 degrees and the helical mesh assembly 160 is rotatedto entrain air into the liquid phase within the barrel 110A, B. Angle Θis selected in order to promote the incorporation of a head of airpresent in at least one barrel of the cartridge 110 into the liquidphase: holding the cartridge in a 45 to 90 degree position relative tovertical (i.e. horizontally or near-horizontally) helps to distributethe head of air along the barrel of the cartridge and aid in easilyentraining the air using the mesh mixer. Once air entrainment iscompleted, the plunger 162 is advanced forward by the piston push rodsand the helical mesh assembly 160 folds like an accordion or simplycompresses down to a low profile to permit dispensing of all orsubstantially all (i.e. greater than 90%) of the contents of the barrel110A, B.

Site Access Method

Delivery systems of the invention can be used in conjunction with siteaccess devices to permit deployment of in situ forming foams into closedcavities, such as the abdominal cavity in cases of internal bleeding,including one or more of the following: abdominal bleeding,junctional/inguinal bleeding, and pelvic bleeding. An exemplaryprocedure to obtain access to the abdominal cavity and insert thedelivery system nozzle into the body will include a skin incision andintroduction of an entry port into the abdomen directly above theumbilicus. The entry port can range from 1.8 mm to 13 mm ID. Thedelivery nozzle will be placed into the entry port thereby providing apathway for the material into the cavity. Detailed steps of thisexemplary procedure include the following:

(1) Perform a small skin nick with a scalpel above the umbilicus(2) Insert entry port (such as a Veress needle with dilator sheath) toabdominal cavity(3) Remove at least a portion of the entry port (e.g. the Veress needlemay be retracted, leaving the dilator sheath in place within thepatient), and dispense lubrication (polyol or similar) into sheath ifrequired.(4) Hold dilating sheath stable in one hand and insert the deliverysystem nozzle into the sheath with the other hand.(5) Advance the nozzle into the abdomen using a slow rocking motion. Anoptional positive stop on the delivery nozzle indicates that the nozzleis in the correct location.(6) Attach nozzle to the delivery system and dispense material.

Devices that may be useful for obtaining access to closed cavities suchas the abdominal cavity include, without limitation, a 6 cm Veressneedle as shown in FIG. 6; a short (e.g. about 5 cm) dilating sheath asillustrated in FIG. 7; or an 11 mm diameter nozzle with a long taper(e.g. about 4.4 cm), as shown in FIG. 8.

Static Mixer

In certain embodiments, a static mixer 130 is used to mix the two liquidphases—which in some cases are characterized by different viscositiesand/or densities, and may be challenging to mix together—prior to theirdeposition in the abdominal cavity. An exemplary static mixer 130 asshown in FIG. 9 consists of a plurality of stacked X-grid elements 131;in the nozzle of FIG. 9, the X-grid elements 131 are stacked at 90degree angles relative to adjacent elements. The X-grid elements 131advantageously promote mixing at the outer walls of the nozzle and havebeen used successfully to mix viscous urethanes, adhesives and foamsystems in other settings. Though X-grid elements are preferred, othermixing means are within the scope of the invention, including staticmeans such as beads, mesh, and patterned static mixer elements havingother shapes, such as helical, quadro, etc., as well as dynamic mixingelements as are known in the art. The mixer 130 can include a pluralityof dispensing apertures 132 at its tip, to permit dispersion ofgas-entrained, mixed in situ forming formulations in multiple directionswithin the body of the patient. For example, the mixer 130 depicted inFIG. 9 includes several dispensing apertures 132 at its dip, fordispensing formulations in multiple directions. In other embodiments,the apertures are distributed evenly around the circumference of thenozzle to allow for placement into the body without specificallyorientating it in a direction. To ensure that the static mixer 130 isinserted within the patient to a useful length—into the body cavitybeing filled, but not far enough to contact the wall of that tissue—themixer optionally includes a stop 133 disposed on the outer surface ofthe static mixer 130 at a useful distance from the tip of the mixer 130.In some cases, the stop 133 is sized and shaped to interlock with aportion of the dilator sheath or other tool used to access the bodycavity, thereby providing a user with a positive indication that the tipof the static mixer 130 is positioned appropriately for the delivery offoam to the body cavity.

Devices according to the embodiments described above advantageouslyprovide for the mixing, aeration, distribution, and injection of foamfor treatment of incompressible wounds. These devices have a number ofimportant qualities: they utilize simple, familiar mechanisms foraeration and injection (turning a crank and/or squeezing a ratchet),simplifying use in challenging settings such as in combat. They do notrequire power or compressed gas, which may lead to failures or safetyhazards on the battlefield. Additionally, devices according to theembodiments described above have small numbers of pieces provided to theuser (5 or less) and can be assembled quickly. The air entrainmentmechanisms described above allow for quick and even distribution of airinto liquid components prior to their deployment. Each step (assembly,site insertion, aeration, dispense) can be performed quickly and safelyin a battlefield environment. However, alternate embodiments utilizingdifferent elements and potentially having different characteristics thanthose described above are also within the scope of the invention, andare described in greater detail below.

External Lead Screw

In an exemplary delivery system 200 according to certain alternateembodiments, a lead screw 280 is used to translate motion of theactuation mechanism 220 to advance the piston push rods 250A, B, therebyurging liquids contained in a dual barrel cartridge 210A, B out of thecartridge 210 and through a static mixer 230. The lead screw 280 can beadvanced using any suitable actuation mechanism 220, including withoutlimitation a crank, ratchet, or socket wrench. Delivery systems 200according to this embodiment are characterized by an advantageouslysimple design, and accordingly simple steps for use, as a singlemechanism is used to both entrain air and deploy the liquids. Forexample, in the unassembled state, the user can take the crank handle(shown in green) place it at the rear of the device and aerate the foam.The user can then remove the crank handle, assemble the lead screw,reposition the crank at the top of the device (as depicted in theassembled drawing) and deploy the liquids by turning the crank. FIG. 11depicts actual prototypes using a socket wrench as an actuationmechanism.

Internal Pulley

In certain embodiments, a pulley mechanism is used as an actuationdevice 220, 221 for either advancing the piston push rods 250 and/or toentrain air into one or more liquid phases within the dual barrelassembly 210. As illustrated in FIG. 12 the pulleys are internal to asingle unit which enables low cube volume and easy packability. Anotheradvantage of this prototype is that a single method of actuation can beused for both aeration and deployment. As an example, and as shown inFIGS. 12 and 13, a socket wrench can be rotated to aerate the fluid;after aeration is complete, a pop-out indicator button in the back endof the system moves from a first position to a second position,indicating a change over from aeration to deployment. The pop-outindicator button is driven by a counter mechanism as described in moredetail below. The indicator button, once it has moved into the secondposition the button can be depressed in order to configure the deliverysystem to dispense the liquid phases from the cartridge. Continuing torotate the socket wrench urges the aerated liquid phase or phasesthrough the mixing tip and into the body.

Piston Pump

Devices according to certain embodiments may utilize a diaphragm pump280 to expel the fluids into the mixing nozzle and deploy theformulation into the body. In an exemplary embodiment, shown in FIGS. 14and 15, an unassembled device comes in three major pieces: a cartridgecontaining a polyol liquid phase, a cartridge containing an isocyanateliquid phase, and a diaphragm pump with a nested handle. As shown insteps 1 and 2 of FIG. 15, the nested handle is removed from thediaphragm pump and inserted into the polyol cartridge. The handle isrotated to entrain air into the polyol liquid phase. Once aeration iscompleted, the crank can be removed and the isocynanate and polyolcartridges can be attached to the diaphragm pump (as shown in step 3 ofFIG. 15). The crank is then attached to the diaphragm pump and used todeploy the liquid phases in the cartridges. As the diaphragm moves fromside to side it draws small amounts of polyol, then isocyante and pushesthem into the flexible tube and through the mixing nozzle. The diaphragmpump creates alternating flows of isocyanate and polyol that are mixedin the nozzle instead of injecting two side by side streams of polyoland isocyanate. A dynamic mixer may provide more efficient mixing when adiaphragm pump dispensing mechanism is used.

Aeration Mechanism

In the embodiment shown in FIG. 16, the cartridge containing the polyolwould be detached in the system, an aeration mesh would be containedinside the cartridge and attached to a pull cord. Pulling the cord(similar to a rip cord on a lawnmower) would turn the aeration meshinside the cartridge and entrain the head of air that is within thecartridge (as depicted in FIG. 16, step 2). The deployment mechanisminto the body is shown as a ratchet mechanism but can consist of any ofthe above mentioned deployment mechanisms.

Portable Compressed Gas

While the embodiments described above have emphasized mechanical meansfor expelling fluid from dual barrel cartridges, other means, such ashydraulic or pneumatic means, can be used. In some embodiments, aportable compressed air cylinder 290 is used to effectuate gasentrainment and/or dispense fluid from the dual-barrel cartridge. Forexample, a portable air cylinder can be used to compress a piston, whichurges fluids from one or more barrels of a cartridge, which fluids arethen mixed by an impeller mechanism. The pressure generated from thecompressed air expels a mixed, gas entrained formulation from the deviceand dispenses it into a site of interest on or within a patient. Theimpeller mechanism can be static (flow driven) or dynamic (driven by amotor or other driving means, including without limitation pneumaticallyby the same compressed air cylinder 290 or a different gas source 291).Compressed-gas driven devices according to the invention may have anumber of advantageous characteristics, including, without limitation:

-   -   Ease of use (press a button to trigger release)    -   Ability to expel more viscous liquids because of use of higher        pressures    -   Ability to modulate to complete dispense in a preset time

In devices according to embodiments of the invention, compressed gas maybe provided by means of pre-pressurized gas cylinders, or in thealternative, a chemical reaction may generate gas within a chamber suchas a cylinder to minimize the danger inherent in transportingpressurized canisters, particularly in remote and dangerous areas suchas battlefields. In preferred embodiments, the chemicals that react togenerate the gas will remain inert until their reaction is triggered bya user, at which point they will rapidly react to generate a volume ofgas sufficient to drive successful deployment of foam within a patient.Any suitable gas generating chemistry may be used in accordance with theinvention, including without limitation a sodium azide (NaN₃) andpotassium nitrate (KNO₃) reaction. Chemical gas sources also permitdelivery systems to be packaged in relatively small pieces for compactstorage and portability, then assembled prior to use. For example, thenozzle and compressed air cylinder can be screwed onto to the handleprior to use. Various compressed gas-driven configurations of thedelivery system are shown in FIGS. 17-20.

Compressed Gas and Bladder Canister Design

In an exemplary embodiment, compressed gas is released and pushes on aplunger that advances within one or more barrels of a multi-barrel fluidchamber in which one or more components of an in situ foamingformulation are contained in separate bladders. The plunger, whenadvanced, pierces the component bladders and forces the componentsthrough a dynamic mixing section and/or a static mixing section beforethe mixture is expelled from the device and on or into the body of apatient. In use, the device is engaged as follows: The handle issqueezed in order to break the seals of the CO2 chamber. Simultaneouslythe multiple bladders that contain components A&B are pierced by aseries of sharp cones. The cones also act as a bulk stage mixing pathfor components A&B. Components A&B merge and are forced into the centraltube. Located inside the central dispensing tube is a dynamic mixingturbine. The bulk mix of A&B is forced through to the distal tip whichcontains a final short phase of static mixer. The mixed components arefinally dispensed into the body through an outlet

While the disclosure above has generally dealt with multi-barrelchambers for in situ forming foam delivery systems, it will beunderstood that the reactive components for forming foams can beseparated by a variety of means, which may be fixed and permanent or,alternatively, temporary and removable. In certain embodiments, adelivery system 300 of the invention includes a chamber 310 containingseparate fluid components 320, 330 of an in situ foaming formulationwhich are, initially, separated by one or more films 340 which arecapable of being ruptured by a rupturing mechanism 350. The device 300includes a hand crank 360 attached, directly or indirectly, to a crankshaft 361 for advancing a plunger 370 forward, thereby bringing the filmor films 340 in contact with the rupturing mechanism and expelling thematerial fluid components 320, 330. An impeller 380 is attached to thecrank shaft 361 and, as the hand crank 360 is rotated, the impeller 380turns and mixes the fluid components 320, 330. A reducing gear 362 canbe interposed between the hand crank 360 and the crank shaft 361 toreduce the numbers of turns of the hand crank 360 required to expel thefluid components 320, 330 and/or to decrease the torque needed to turnthe hand crank and mix fluid components 320, 330 which have highviscosity, or which form a high viscosity mixture.

Devices according to this embodiment have several advantageouscharacteristics, including without limitation (i) Hand operation such asa lever or twisting motion could ease deployment because of mechanicalleverage; A winding spring mechanism can be used to generate forceneeded to dispense the material and allow the medic to press a releasebutton to deploy the material into the body; (iii) A battery drivenshaft could also be incorporated into the delivery system. (iv) Reducinggears can be used to get a 16:1 “turn to dispense” ratio. Potentiallyyou can mix and expel the material at the same time or using a singletype of motion; (v) The mixing impeller(s) are can provide veryefficient mixing and does not require high pressures such as with thestatic mixing nozzles; (vi) The impellers may release dissolved gases tocreate the required nucleation sites for foaming; (vii) Coaxialplacement of part A and B in the cartridge to reduce overall volume.Exemplary reducing gears and impellers are shown in FIGS. 21, 22, and23.

Alternate Mixing Concepts: Mixer Plate Mixing Element

In certain embodiments of the invention, the mixing of fluid componentsis achieved using mixing areas characterized by a relatively largesurface areas (as opposed to the relatively small surface area of astandard static mixer) to reduce the back pressure required for uniformmixing. In preferred embodiments, a fluid chamber 400 contains fluidcomponents are arranged in concentric subchambers 410, 420 sealed attheir distal ends (i.e. the ends nearest the outlet of the deliverysystem) with a plastic membrane. The membrane seal is broken by pressurewhich can be a user-operated actuator action such as a squeeze or pushof the grey part shown in FIG. 25. In some embodiments, a check valve ora one way valve is utilized rather than a puncturable plastic membrane;the valve opens upon the application of pressure. The two components aremixed by pushing the liquid phases into the convoluted paths of thelarge mixing area 430 at the distal end of the container (FIG. 26). Thedistal end of the chamber 400 optionally includes walls 450 extendingaway from the main surface of the chamber at an angle such as 90 degreesto define a series of passageways 460 that repeat from the outercircumference to the inner circumference of the distal end of thechamber, as shown in FIG. 26. A series of color images shows two liquidparts (shown in red and green of FIG. 27) moving through the convolutedpathway and mixing and/or folding into each other.

In a preferred embodiment, the mixing area comprises two concentricplates with an outer mixing plate 430 rotating in a first direction andan inner mixing plate 440 rotating in a second direction. FIG. 28. Eachof the mixing plates optionally includes a plurality of apertures 460 topermit fluid to flow or move through each mixing plate. Exemplary mixingplate and chamber arrangements are shown in FIGS. 28-29.

Alternate Canister Designs

In this concept the suggested layout of the canister can help withefficient mixing of parts A and B and combined with an impeller wouldprovide a reproducible mixing method for polymers eliminating the needfor mixing nozzles (FIG. 30).

In another embodiment, rather than utilizing a crushable or rupturablemembrane, an iris mechanism is used to keep components A and B separateuntil ready for use. The iris mechanism separates each component A, Binto its own respective compartment, and as the iris mechanism is openedparts A and B are brought into fluid contact with one another. The irismechanism can also be used to mix parts A and B by opening and closingthe iris several times, e.g. via a quick turn/twist with the hands priorto dispensing into the body. Images of this concept are shown below(FIG. 31):

Alternate Site Insertion Method (Cutting Needle)

The distal tip of the delivery system, in certain embodiments, includesa spring-actuated cutting needle 500 that can be used to access closedbody cavities such as the abdominal cavity in which foam deployment isdesired. In preferred embodiments, such as the embodiment shown in FIG.32, the distal tip includes a blunt end 510 comprising one or moreapertures 520 for the expulsion of in situ forming formulations. Aspring-actuated cutting needle 530 is disposed, at rest, at a fixeddistance from the blunt end such that, when the tip is pressed into theskin of a patient, the cutting needle advances relative to the bluntend, thereby exposing the cutting needle so that the skin and any tissuelayers overlying the body cavity in which in situ forming foamdeployment is desired can be penetrated.

Motorized Mixer with Compressed Gas Dispenser

In animal studies, the inventors have used a motorized mixer inconjunction with compressed gas to mix and dispense the liquid phases.This system can be miniaturized and adapted for battlefield use.According to certain embodiments of the invention, compressed CO2cylinders are used to power both the motor and the piston, though insome embodiments, compressed gas is provided by a chemical reaction asdiscussed above.

In one example, the following components are used:

-   -   Motor: Micro Motors Inc. Santa Ana, Calif.    -   Model #MMR0014, RPM 1750 @ 90 psi, Tachometer reading 1500 RPM        at 80 psi.    -   Stall Torque 110 inch ounces.    -   Piston: Bimba    -   Model #SR-044-D, max pressure 100 psi, ¾″ diameter, 4″ length.    -   Dimensions of overall system with nozzle folded: 12×8×6 inches

Images of the design are shown in FIG. 33 (gas cylinders are notpictured).

CAD images of the system are shown in FIG. 34. In both embodiments, thedevice 600 includes one or more fluid chambers 610 as discussed above,as well as a motorized actuator 620, a mixing nozzle 630, and pistons650 that are advanced by the motorized actuator 620 to compress thefluid chambers 610, thereby evacuating the in situ foaming formulationthrough the mixing nozzle 630 and into the body of the patient. Aerationand/or mixing are aided by the motorized mixer assembly 660, whichconnects to the mixing nozzle 630.

Connection Between the Device and the Dispensing Tip

In some embodiments, the mixing tip 630 of the device is connected tothe motorized mixer 660 as shown in FIG. 35. The connection between thedispensing tip 630 and the motorized mixer advantageously does notrequire alignment of the mixing element 631 and drive shaft 661. Mixingelements 632 are held in between the recesses 662 in the drive shaft661. The drive shaft 661 is contoured, spring loaded and rotates toaccept the mixing elements at any angle. The nut 633 twists and locks inposition. An o-ring provides a seal for the polyol and isocyanate.

Multi-Prong Delivery Catheter

In some embodiments, dispersion of air-entrained in situ formingformulations within closed cavities is improved by the use ofmulti-nozzle dispersal tips. In some embodiments, a multi-nozzledispersal tip includes a plurality of catheters having multipleapertures for discharging fluids into a body cavity. FIG. 36 depicts afirst exemplary multi-prong tip 700 (Prototype #1). The catheters arereinforced with flat stainless steel braids and over extruded with aPebax layer. The end of each catheter optionally includes a pig tailcurve 710 so that the catheter is atraumatic during insertion. Theexemplary multi-prong tip 700 shown in FIG. 36 advantageously depositsmaterial on both sides of the spine when used in the abdominal cavity,thereby allowing the foam to reach the vena cava and aorta. However,small diameter catheters may have difficulty tracking to the sites ofabdominal gutters.

Prototypes 2-4 (shown in FIG. 37A-C) have larger diameters, improvingtheir ability to track to gutters of the abdomen.

Prototype #2 has a 5 mmID×8 mmOD tube with end hole and includes aballoon 720 to help keep the tip in position. Prototype #3 includes a 4mmID×7 mmOD tube with 8 radially distributed end holes 730. Thecatheters of prototype #3 are made of nylon and are stiffer thanprototype 2. Prototype #4 also includes a 4 mmID×7 mmOD nylon tube buthas 24 holes 740 along the length of the tube.

Lock Out Mechanism

Formulations that are not fully aerated may not efficiently promotehemostasis, it is desirable in some instances to prevent the delivery ofunaerated or partially aerated formulations delivered using deliverysystems of the invention. Thus, in preferred embodiments, the deliverysystem includes a lockout mechanism to prevent the deployment offormulations until aeration is complete. As shown in FIGS. 38A and 39,in an exemplary embodiment of the invention, a delivery system 800 isprovided to users in multiple pieces including a nozzle 840 and anactuator 850, along with a cartridge 810 and an aerator 820 which areprovided as a single unit held together with a u-clamp 830. Thecartridge includes at least two chambers 811, 812 which contain andseparate the isocyanate and polyols components of the foamingformulation. Each chamber 811, 812 includes a plunger 813 for evacuatingthe contents of the chamber, and each chamber also optionally includes aone-way valve 814 disposed opposite the plunger, to ensure that fluidsthat are evacuated from the chambers 811, 812 cannot be returned intothe system 800. In addition, at least one of the chambers 811, 812includes a mixer 815 such as the helical mesh and shaft arrangementdescribed above; the plunger 813 in this chamber is cannulated toaccommodate the shaft of the mixer 815. The shaft of the mixer, in turn,is connected (optionally via a reducing gear system as described above)to a hand-crank 816 or other mechanical actuator for aerating at leastone of the fluid phases of the in situ foaming composition. The system800 is initially provided to the user in a “locked” configuration suchthat the aerator and cartridge cannot be disconnected until certain usersteps, including aeration, are completed. In one such arrangement, auser is required to aerate the foaming formulation by cranking a handlethrough a minimum number of turns before the device can be assembled topermit injection of the formulation into the body. In particular, theaerator 820 contains pins 821 that initially extend into the u-clamp830. Once the threshold number of turns is reached, a spring mechanismpulls back the pins and allows the u-clamp to be removed and the aeratorto be separated from the cartridge. At the same time, a ready indicatoroptionally changes status, (e.g. changes from black to white) tovisually or audibly indicate to the user that aeration is complete. Oncethe cartridge is detached it can then be attached to the handle anddeployed into the body.

Aerator Design with Ready Indicator

With respect to the aerator and the ready indicator, in an exemplarydelivery system shown in FIGS. 41-42 the lockout mechanism and readyindicator form parts of an integrated system providing feedback to auser that the formulation is fully aerated and ready to be dispensed. Inthe pictured embodiment, at least one spring-loaded pin 821 (circledthroughout the various views) is configured to reversibly mate with anindicator assembly 822. In a closed configuration, shown in FIGS. 41Band 42B and D, the indicator assembly 822 is in a “not-ready” state inwhich a portion of the assembly 822 is positioned so as to preventretraction of the pin 821. After the impeller assembly 815 has movedthrough a pre-sent number of turns, however, the indicator assembly 822is displaced so as to permit the pin or pins 821 to retract into thebody of the cartridge, (shown in FIGS. 41A and 42A and C) permittingremoval of the U-clamp and dispensing of the aerated formulation intothe body.

Dose Slider

It may also be desirable, in some instances, to tailor the quantity offoaming formulation delivered via a delivery system of the invention toa specific application or patient. For instance, an exemplary deliverysystem 900 includes a dose slider mechanism as shown in FIGS. 43-44,which permits a user to administer relatively less formulation to anindividual in a lower weight or height percentile or to administerrelatively more to an individual in a higher percentile. The dose slider910 is an adjustable slide that is part of the handle assembly and whichprevents the movement of the piston rods or pistons through their fullrange. In the embodiment shown in FIGS. 43-44, the dose slider islocated on a piston rod 920 that is attached to the friction drive 930.The rod optionally includes markings 921 that indicate, eithersubjectively (e.g. small, medium and large) or objectively (e.g.volumetric indications) an amount of formulation that will be delivered.A user can move the slider 910 to a selected marking 921, therebyselecting the volume to be delivered. The slider 910 resides on thepiston rods 920 behind the friction drive 930 and serves a positive stopfor the friction drive 930. In particular, the slider prevents thefriction drive from advancing forward and dispensing formulation.

While the examples presented above have focused on multi-componentformulations for generating in-situ forming foams, those of skill in theart will appreciate that they can be adapted to function withsingle-part foaming formulations, and such adaptations are within thescope of the present invention.

The phrase “and/or,” as used herein should be understood to mean “eitheror both” of the elements so conjoined, i.e., elements that areconjunctively present in some cases and disjunctively present in othercases. Other elements may optionally be present other than the elementsspecifically identified by the “and/or” clause, whether related orunrelated to those elements specifically identified unless clearlyindicated to the contrary. Thus, as a non-limiting example, a referenceto “A and/or B,” when used in conjunction with open-ended language suchas “comprising” can refer, in one embodiment, to A without B (optionallyincluding elements other than B); in another embodiment, to B without A(optionally including elements other than A); in yet another embodiment,to both A and B (optionally including other elements); etc.

As used in this specification, the term “substantially” or“approximately” means plus or minus 10% (e.g., by weight or by volume),and in some embodiments, plus or minus 5%. Reference throughout thisspecification to “one example,” “an example,” “one embodiment,” or “anembodiment” means that a particular feature, structure, orcharacteristic described in connection with the example is included inat least one example of the present technology. Thus, the occurrences ofthe phrases “in one example,” “in an example,” “one embodiment,” or “anembodiment” in various places throughout this specification are notnecessarily all referring to the same example. Furthermore, theparticular features, structures, routines, steps, or characteristics maybe combined in any suitable manner in one or more examples of thetechnology. The headings provided herein are for convenience only andare not intended to limit or interpret the scope or meaning of theclaimed technology.

Certain embodiments of the present invention have described above. Itis, however, expressly noted that the present invention is not limitedto those embodiments, but rather the intention is that additions andmodifications to what was expressly described herein are also includedwithin the scope of the invention. Moreover, it is to be understood thatthe features of the various embodiments described herein were notmutually exclusive and can exist in various combinations andpermutations, even if such combinations or permutations were not madeexpress herein, without departing from the spirit and scope of theinvention. In fact, variations, modifications, and other implementationsof what was described herein will occur to those of ordinary skill inthe art without departing from the spirit and the scope of theinvention. As such, the invention is not to be defined only by thepreceding illustrative description.

1. A medical device, comprising: a fluid cartridge comprising at leastone chamber and at least one piston, wherein a volume of the chamber isdetermined by a position of the at least one piston; at least oneimpeller located within the at least one chamber a static mixer in fluidcommunication with the chamber, the static mixer including a tipconfigured for insertion into a body of a patient; and a first actuatoradapted to move at least one of the impeller and the piston.
 2. Themedical device of claim 1, wherein moving the first actuator moves thepiston, decreasing a volume of the chamber.
 3. The medical device ofclaim 1, wherein moving the first actuator aerates a fluid in at leastone chamber of the cartridge.
 4. The medical device of claim 2, whereinthe first actuator is one of a squeeze handle, a crank handle, aratchet, or a piston pump.
 5. The medical device of claim 3, wherein thefirst actuator is configured to reversibly couple to one or more of theat least one piston and the at least one impeller.
 6. The medical deviceof claim 1, further comprising a cylinder loaded with compressed gas,wherein activation of the first actuator causes the evacuation ofcompressed gas from the cylinder and one of (a) the advancement of thepiston within the at least one chamber, thereby expelling the contentsof the fluid cartridge, or (b) the movement of the impeller within theat least one chamber, thereby aerating a fluid within the cartridge. 7.The medical device of claim 1, wherein the impeller comprises a mesh. 8.The medical device of claim 1, wherein a rim of the impeller contacts awall of the chamber.
 9. The medical device of claim 1, wherein thestatic mixer comprises a substantially cylindrical outer shell defininga lumen, the outer shell having a tapered end, the tapered endcomprising a plurality of apertures through the outer shell, and aplurality of mixing elements disposed within the lumen.
 10. The medicaldevice of claim 9, wherein the mixing elements are selected from thegroup consisting of X-grids, beads, and mesh.
 11. The medical device ofclaim 1, further comprising a lockout mechanism reversibly coupled tothe fluid cartridge, wherein (a) the lockout mechanism is moveablebetween a first configuration which prevents the movement of the atleast one piston and a second configuration which permits the movementof the at least one piston and (b) the lockout mechanism moves from thefirst configuration to the second configuration after the impeller hasundergone a predetermined number of rotations within the at least onechamber.
 12. The medical device of claim 1, further comprising amoveable dose selector which is configured to stop the movement of theat least one piston beyond a position determined by a position of themoveable dose selector.
 13. A system for treating a hemorrhage,comprising: a medical device comprising: a fluid cartridge comprising atleast one chamber and at least one piston, wherein a volume of thechamber is determined by a position of the piston; at least one impellerlocated within the at least one chamber; a static mixer adapted tofluidly communicate with the at least one chamber, the static mixerincluding a tip configured for insertion into a body of a patient; and afirst actuator adapted to move at least one of the impeller and thepiston; and a formulation configured to form, within the body of apatient, a polymer foam, the formulation disposed within the fluidcartridge of the medical device.
 14. The system of claim 13, whereinmoving the first actuator moves the piston, decreasing a volume of thechamber.
 15. The system of claim 13, wherein moving the first actuatormoves the impeller, thereby entraining air into the formulation.
 16. Thesystem of claim 15, wherein the first actuator is configured toreversibly couple to the at least one impeller and the at least onepiston.
 17. The system of claim 13, wherein (a) the formulationcomprises first and second fluid components, each component in aseparate chamber of the fluid cartridge, and (b) the static mixer isfluidly connected to each of the separate chambers such that, when theat least one piston is advanced, the first and second fluid componentsare expelled from the separate chambers and pass through the staticmixer.
 18. The system of claim 13, wherein the impeller comprises amesh.
 19. The system of claim 13, wherein a rim of the impeller contactsa wall of the chamber.
 20. The system of claim 13, wherein the staticmixer comprises a substantially cylindrical outer shell defining alumen, the outer shell having a tapered end, the tapered end comprisinga plurality of apertures through the outer shell, and a plurality ofmixing elements disposed within the lumen.
 21. The system of claim 13,further comprising a lockout mechanism reversibly coupled to the medicaldevice, wherein (a) the lockout mechanism is moveable between a firstconfiguration which prevents the movement of the at least one piston anda second configuration which permits the movement of the at least onepiston and (b) the lockout mechanism moves from the first configurationto the second configuration after the impeller has undergone apredetermined number of rotations within the at least one chamber. 22.The system of claim 13, wherein the medical device includes a moveabledose selector which is configured to stop the movement of the at leastone piston beyond a position determined by a position of the moveabledose selector.